1. Field of the Invention
This invention relates to a method of producing .gamma.-globulin for intravenous injection.
2. Prior Art
Gamma globulin has been widely used for the prophylaxis and therapy of diseases caused by various kinds of virus and bacteria. It has, however, been administered only intramuscularly, since intravenous administration may cause serious adverse reactions, such as a sudden decrease in blood pressure, chill, vomiting, pyrexia, cyanosis or shock. In order to raise the antibody titer in blood quickly, however, it is clinically more advantageous to inject .gamma.-globulin intravenously rather than intramuscularly, since an effective dose of .gamma.-globulin is smaller intravenously than intramuscularly, and the .gamma.-globulin so injected can be utilized more effectively. Intramuscular injection is also undesirable for other reasons; for example, it tends to cause local decomposition of .gamma.-globulin at the site of injection, while intramuscular injection of a large quantity of .gamma.-globulin may cause local pain or induration of the muscle.
The process of the adverse reactions caused by intravenous administration of .gamma.-globulin is generally explained as follows: some part of .gamma.-globulin molecules aggregate during its purification, and these aggregates cause nonspecific complement activation in the current which is different from antigen-antibody reaction. Various attempts have, therefore, been made to provide a method of producing .gamma.-globulin which can be administered intravenously without causing activation of complement, i.e., .gamma.-globulin having a reduced anticomplementary activity, which does not cause any adverse reactions. Several methods have been proposed for producing such .gamma.-globulin, for example, (1) partial degradation of .gamma.-globulin with a proteolytic enzyme (H. Koblet et al., Vox Sang., 13, 92 (1967), and L. A. Hanson et al., Int. Arch. Allergy, 31, 380 (1967)), (2) chemical modification of .gamma.-globulin (Vox Sang., 28, 422 (1975)), (3) removal of the aggregates from .gamma.-globulin (U.S. Pat. No. 4,093,606, and Japanese Patent Laid-Open Nos. 81519/74 and 101516/74), (4) addition of one or more substances for preventing regeneration of aggregates in .gamma.-globulin which has been freed from aggregates (Japanese Patent Laid-Open Nos. 91321/76 and 47515/78), or (5) addition of one or more substances which can dissociate the aggregates in .gamma.-globulin and at the same time can prevent regeneration of aggregates in it (Japanese Patent Laid-Open No. 20124/79). Among these methods, the degradation of .gamma.-globulin with a proteolytic enzyme such as pepsin or plasmin to reduce its anticomplementary activity was first proposed and has long been employed as an effective method for practical purposes. This method, however, lowers the opsonic activity of .gamma.-globulins since those enzymes bring about partial decomposition of its molecular structure. Moreover, if pepsin is used as a proteolytic enzyme, the resulting .gamma.-globulin is known to possess an extremely short half-life in the current.